EP0540782B1 - Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations - Google Patents

Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations Download PDF

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Publication number
EP0540782B1
EP0540782B1 EP91202616A EP91202616A EP0540782B1 EP 0540782 B1 EP0540782 B1 EP 0540782B1 EP 91202616 A EP91202616 A EP 91202616A EP 91202616 A EP91202616 A EP 91202616A EP 0540782 B1 EP0540782 B1 EP 0540782B1
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group
direct bond
hydroxy
independently represent
mercapto
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EP0540782A1 (de
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Louis H. Cohen
Jacobus H. Van Boom
Gijsbert A. Van Der Marel
Adrianus P. R. M. Valentijn
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Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Universiteit Leiden
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Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Universiteit Leiden
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Priority to ES91202616T priority patent/ES2133278T3/es
Priority to DE69131199T priority patent/DE69131199T2/de
Priority to AT91202616T priority patent/ATE179607T1/de
Priority to DK91202616T priority patent/DK0540782T3/da
Application filed by Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO, Universiteit Leiden filed Critical Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is in the field of medicine. More specifically, it relates to a novel use of polyisoprenyl pyrophosphate analogues in interfering with certain biochemical processes.
  • polyisoprenyl pyrophosphate analogues in interfering with certain biochemical processes.
  • analogues wherein the polyisoprenyl group is farnesyl or geranylgeranyl.
  • the polyisoprenyl group that was attached to a protein was identified as either farnesyl (C 15 ) or geranylgeranyl (C 20 ), probably depending on the recognition of the C-terminal amino acid sequence of the proteins involved.
  • G proteins play a role in the receptor-mediated transduction of signals (such as growth modulation signals) over the plasma membrane, and other isoprenylated proteins, not yet identified, may have a function in cell cycle progression. There is some evidence as well that GTP binding proteins are involved in the regulation of intracellular protein traffic and secretion. There is even some suggestion that isoprenylated proteins play a role in the translational control of HMG-CoA reductase, the rate limiting enzyme of the isoprene and subsequent cholesterol synthesis.
  • FPP farnesyl-pyrophosphate
  • farnesyl pyrophosphate is a substrate in a key step in the synthesis of cholesterol.
  • the synthesis of squalene from farnesyl pyrophosphate is effected by the enzyme squalene synthase.
  • squalene is formed by formation of a bond between two farnesyl groups in a reaction that requires a synthase.
  • certain farnesyl pyrophosphate analogues have been described that can be used for inhibiting said step in the cholesterol synthesis, for use in the treatment of hypercholesterolaemia.
  • Such a process differs from the protein isoprenylation in which other enzymes are required for the isoprenylation, e.g. the farnesylation, or the geranylgeranylation of proteins.
  • polyisoprenyl pyrophosphate analogue for preparing a pharmaceutical composition suitable for inhibiting protein isoprenylation, the specific polyisoprenyl pyrophosphate analogues having formula 1, wherein:
  • the present invention further relates to a pharmaceutical composition for inhibiting protein isoprenylation, containing a polyisoprenyl pyrophosphate analogue according to formula 1, wherein X 3 -A 3 -X 4 -A 4 represents an oxygen atom or a methyleneoxy group, or a pharmaceutically acceptable salt thereof, with the proviso that the polyisoprenyl pyrophosphate analogue is not polyisoprenyl pyrophosphate itself, together with a carrier adapted for protein isoprenylation inhibiting purposes.
  • a pharmaceutical composition for inhibiting protein isoprenylation containing a polyisoprenyl pyrophosphate analogue according to formula 1, wherein X 3 -A 3 -X 4 -A 4 represents an oxygen atom or a methyleneoxy group, or a pharmaceutically acceptable salt thereof, with the proviso that the polyisoprenyl pyrophosphate analogue is not polyisoprenyl pyr
  • the group Pren generally represents an acyclic terpenoid group, i.e. a hydrocarbon group consisting of C 5 isoprenylene (2-methyl-1,4-but-2-enylene) units, in particular 2-6 of such isoprenylene units.
  • One or more of these isoprenylene units may be replaced by isomeric units such as 2-methyl-1,2-but-3-enylene or 2-methylene-1,4-butylene.
  • the C-C double bond in these units may be cis and/or trans , but is preferably trans .
  • One or more of the double bonds may be hydrogenated resulting in a terpenoid group having less than one double bond per C 5 moiety, or alternatively one or more of the single C-C bonds may be dehydrogenated resulting in a terpenoid group having more than one double bond per C 5 moiety.
  • the terpenoid group contains one C-C double bond per C 5 moiety.
  • the terpenoid group may be substituted e.g. by halogen, in particular fluorine, methoxy or additional methyl; on the other hand one or more methyl side groups may be lacking.
  • the terpenoid group is a C 10 -C 20 group (monoterpenic, sesquiterpenic or diterpenic).
  • Examples of monoterpenic groups (C 10 ) are geranyl, neryl, linalyl, ocimenyl, myrcenyl and citronellyl.
  • Examples of sesquiterpenic groups are ⁇ -farnesyl, ⁇ -farnesyl, nerolidyl and dihydro derivatives thereof.
  • Examples of diterpenic groups are geranyl-geranyl, geranyl-linalyl and hydrogenated derivatives thereof such as geranyl-citronellyl and phytyl.
  • Preferred terpenoid groups are farnesyl and geranyl-geranyl. Most preferred is all - trans - ⁇ -polyisoprenyl.
  • the two groups represented by X 1 -A 1 -X 2 -A 2 and X 3 -A 3 -X 4 -A 4 in formula 1 are in particular each a direct bond between the terpenoid group and the phosphorus atom or a heteroatom such as oxygen, nitrogen or sulphur, or an alkylene group, or an alkylene group flanked by one or two heteroatoms or a heteroatom flanked by two alkylene groups.
  • the heteroatom is preferably oxygen or sulphur, most preferably oxygen.
  • the alkylene group may have substituents such as fluorine, chlorine, methyl, hydroxy or methoxy, and it is preferably methylene.
  • the group X 1 -A 1 -X 2 -A 2 is more in particular a direct bond, a methylene group, a methyleneoxy group or a substituted methylene of methyleneoxy group.
  • the group X 3 -A 3 -X 4 -A 4 is more in particular an oxygen atom, a methylene group, a methyleneoxy group or a substituted methylene or methyleneoxy group.
  • the multiplicator n may have a value of 1 or 2, representing for example pyrophosphates (diphosphonates), and triphosphates respectively, but is preferably 1.
  • the groups Y 1 , Y 2 and Y 3 in formula 1 preferably comprise one or more hydrophilic groups, such as hydroxy, hydroxyethyl, mercapto or amino.
  • at least one of Y 1 , Y 2 and Y 3 , and more in particular at least two of Y 1 , Y 2 and Y 3 are hydroxy, mercapto or salts thereof; the remaining ones may for example be methyl, ethyl, phenyl, benzyl, methoxy, farnesyloxy, phenoxy, cyclohexyloxy, methylthio, dimethylamino etc.
  • Y 1 and Y 2 or Y 1 and Y 3 may be connected to each other, e.g.
  • Y 1 , Y 2 and Y 3 represents hydroxy or mercapto
  • the resulting phosphoric, phosphonic or phosphinic acid may be in the form of a pharmaceutically acceptable salt, e.g. an ammonium, substituted ammonium, alkali metal or alkaline earth metal salt.
  • Preferred compounds are those wherein Y 1 , Y 2 and Y 3 each represent hydroxy or mercapto, preferably hydroxy, and in particular the salts thereof.
  • the groups Z 1 and Z 2 in formula 1 are oxygen or sulphur, preferably oxygen.
  • poylisoprenyl pyrophosphate analogues examples include farnesylmethylphosphonophosphate (1), farnesylmethylphosphono-methylphosphonate (2), farnesylphosphonophosphate (3), farnesylphosphono-methylphosphonate (4) and farnesylthiophosphonophosphate and the corresponding geranylgeranyl compounds, with a preference for compounds (1) and (3).
  • polyisoprenyl pyrophosphate analogues to be used according to the invention can be prepared in a manner which is known per se. For example, they may be prepared by the method described by Valentijn et al, Synlett . 1991 , 663-664, or by the methods described in European patent applications 324421 and 356866.
  • the polyisoprenyl pyrophosphate analogues according to the invention are capable to specifically inhibit the protein isoprenylation at low dosage amounts (IC 50 ⁇ 1 ⁇ M) and that squalene synthesis is not inhibited significantly at these dosage amounts.
  • the FPP analogue concentration will be selected in order to disturb other processes which use FPP or similar substrates, e.g. the squalene synthesis, as little as possible. Therefore, preferred FPP analogues to be used according to the invention are analogues that are specific for the isoprenylation reaction to be inhibited.
  • the compounds (1) and (3) mentioned above can inhibit p21 ras : farnesyl transferase when applied in dosage amounts that are too small for said analogues to inhibit squalene synthase, thereby inhibiting farnesylation of p21 ras without inhibiting squalene synthesis.
  • polyisoprenyl pyrophosphate analogues described above are useful as an active substance in a pharmaceutical composition intended to interfere with protein isoprenylation. As such, they are useful as inhibitors in processes such as oncogenesis and other unwanted cell proliferation, and furthermore as suppressants of aberrant high signal transduction.
  • compositions to be prepared using the polyisoprenyl pyrophosphate analognes according to the invention may be formulated in a usual way, e.g. by associating the polyisoprenyl pyrophosphate analogue with a suitable solid or liquid carrier and optional adjuvants or other active components.
  • the composition may be suitable for oral administration (capsule, pill, tablet, gel, powder, sachet, syrup, solution, dispersion etc.) or may be an injectable solution or another administration form.
  • the composition may be administered to mammalians including man, in a dose which depends on the particular purpose of the administration, the body weight and other conditions well known to the skilled person. A dose can be administered in a single dosage or in several daily dosages.
  • Methyl phosphonic dichloride (6.65 g, 50 mmol) as dissolved in freshly distilled ether (80 ml) and cooled to 0°C. Then morpholine (8.72 ml, 100 mmol) in 20 ml ether was added dropwise over a period of 2 h and stirring was continued overnight at 0°C. The salts were removed by filtration and the solvent was evaporated. The residue was dissolved in 50 ml ether and treated with a mixture of methanol (3.82 ml, 100 mmol) and triethylamine (6.97 ml, 50 mmol) in 50 ml ether at 0°C.
  • N-Chlorosuccinimide (0.66 g, 4.95 mmol) was dissolved in 20 ml of dry CH 2 Cl 2 under a nitrogen atmosphere. The solution was cooled to -30°C and 0.37 ml dimethyl sulphide (5 mmol) was added. The mixture was allowed to warm to 0°C before it was cooled to -40°C. Then farnesol (1 g, 4.5 mmol) dissolved in 2.5 ml CH 2 Cl 2 was added dropwise to the mixture over a period of 3 minutes. The reaction mixture was warmed to 0°C in 1 h, at which temperature it was maintained for another hour.
  • IC 50 -values were obtained for the compounds 1 and 3 respectively for inhibition of the enzyme squalene synthase in rat liver microsomal preparations.
  • the IC 50 -values were 480 ⁇ M and 120 ⁇ M respectively.

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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (10)

  1. Verwendung eines Polyisoprenylpyrophosphat-Analogons zur Herstellung einer pharmazeutischen Zusammensetzung, die zur Inhibierung von Protein-Isoprenylierung geeignet ist, wobei das Polyisoprenylpyrophosphat-Analogon die Formel 1
    Figure 00130001
    aufweist, worin:
    Pren eine C10-C30-Terpenoid-Gruppe oder ein Derivat davon darstellt;
    A1, A2, A3 und A4 unabhängig eine direkte Bindung oder eine C1-C4-Alkylen- oder -Alkenylengruppe, gegebenenfalls mit Substituenten, die aus Methyl, Hydroxy, Methoxy, Mercapto, Methylthio, Amino, Methylamino, Dimethylamino und Halogen ausgewählt sind, darstellen;
    X1, X2, X3 und X4 unabhängig eine direkte Bindung, Sauerstoff, Schwefel, Imino oder Methylimino darstellen, mit der Maßgabe, daß, falls A1 eine direkte Bindung darstellt, X2 ebenfalls eine direkte Bindung darstellt und umgekehrt, und falls A3 eine direkte Bindung darstellt, X4 ebenfalls eine direkte Bindung darstellt und umgekehrt;
    Y1, Y2 und Y3 unabhängig Hydroxy, Alkoxy, Mercapto, Alkylthio, Amino, Mono- oder Dialkylamino, Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Aryl oder Arylalkyl darstellen, wobei Alkyl, Alkoxy, Alkenyl und Alkinyl linear oder verzweigt sind und 1-6 Kohlenstoffatome aufweisen und Substituenten aufweisen können, die aus Hydroxy, Methoxy, Mercapto, Methylthio, Amino, Methylamino, Dimethylamino und Halogen ausgewählt sind, Cycloalkyl 3-8 Kohlenstoffatome aufweist, Aryl carbocyclisch oder heterocyclisch mit 5-10 Ringatomen ist und Cycloalkyl und Aryl Substituenten aufweisen können, die aus Methyl, Hydroxy, Methoxy und Halogen ausgewählt sind, wobei eines von Y1, Y2 und Y3 auch eine C7-C30-Alkyl- oder -Alkenylgruppe, einschließlich einer C10-C30-Terpenoid-Gruppe, darstellen kann;
    Z1 und Z2 unabhängig Sauerstoff oder Schwefel darstellen; und
    n 1 oder 2 ist;
    oder eines pharmazeutisch annehmbaren Salzes davon;
    mit der Maßgabe, daß das Polyisoprenylpyrophosphat-Analogon nicht Polyisoprenylpyrophosphat selbst ist.
  2. Verwendung nach Anspruch 1, worin die Gruppe X3-A3-X4-A4 ein Sauerstoffatom oder eine Methylenoxygruppe darstellt.
  3. Verwendung nach Anspruch 1 oder 2, worin Pren eine Farnesyl- oder Geranyl-Geranyl-Gruppe darstellt.
  4. Verwendung nach irgendeinem der Ansprüche 1-3, worin A1 und A3 unabhängig eine direkte Bindung oder eine Methylengruppe darstellen und mindestens zwei von Y1, Y2 und Y3 Hydroxy oder Mercapto oder ein Salz davon sind; und n = 1.
  5. Verwendung nach irgendeinem der Ansprüche 1-4, worin Y1, Y2 und Y3 Hydroxy oder Mercapto oder ein Salz davon sind.
  6. Verwendung nach irgendeinem der vorhergehenden Ansprüche, worin die pharmazeutische Zusammensetzung zur Prophylaxe und/oder Behandlung von Karzinomen geeignet ist.
  7. Verwendung nach irgendeinem der vorhergehenden Ansprüche, worin die pharmazeutische Zusammensetzung zur Inhibierung der Isoprenylierung eines ras-Proteins geeignet ist.
  8. Pharmazeutische Zusammensetzung, die zur Inhibierung von Protein-Isoprenylierung geeignet ist, enthaltend ein Polyisoprenylpyrophosphat-Analogon der Formel 1:
    Figure 00150001
    worin:
    Pren eine C10-C30-Terpenoid-Gruppe oder ein Derivat davon darstellt;
    A1 und A2 unabhängig eine direkte Bindung oder eine C1-C4-Alkylen- oder -Alkenylengruppe, gegebenenfalls mit Substituenten, die aus Methyl, Hydroxy, Methoxy, Mercapto, Methylthio, Amino, Methylamino, Dimethylamino und Halogen ausgewählt sind, darstellen;
    X1 und X2 unabhängig eine direkte Bindung, Sauerstoff, Schwefel, Imino oder Methylimino darstellen, mit der Maßgabe, daß, falls A1 eine direkte Bindung darstellt, X2 ebenfalls eine direkte Bindung darstellt und umgekehrt;
    X3-A3-X4-A4 ein Sauerstoffatom oder eine Methylenoxygruppe darstellt;
    Y1, Y2 und Y3 unabhängig Hydroxy, Alkoxy, Mercapto, Alkylthio, Amino, Mono- oder Dialkylamino, Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Aryl oder Arylalkyl darstellen, wobei Alkyl, Alkoxy, Alkenyl und Alkinyl linear oder verzweigt sind und 1-6 Kohlenstoffatome aufweisen und Substituenten aufweisen können, die aus Hydroxy, Methoxy, Mercapto, Methylthio, Amino, Methylamino, Dimethylamino und Halogen ausgewählt sind, Cycloalkyl 3-8 Kohlenstoffatome aufweist, Aryl carbocyclisch oder heterocyclisch mit 5-10 Ringatomen ist und Cycloalkyl und Aryl Substituenten aufweisen können, die aus Methyl, Hydroxy, Methoxy und Halogen ausgewählt sind, wobei eines von Y1, Y2 und Y3 auch eine C7-C30-Alkyl- oder -Alkenylgruppe, einschließlich einer C10-C30-Terpenoid-Gruppe, darstellen kann;
    Z1 und Z2 unabhängig Sauerstoff oder Schwefel darstellen; und
    n 1 oder 2 ist;
    oder ein pharmazeutisch annehmbares Salz davon;
    mit der Maßgabe, daß das Polyisoprenylpyrophosphat-Analogon nicht Polyisoprenylpyrophosphat selbst ist;
    zusammen mit einem Träger, der für Zwecke der Inhibierung von Protein-Isoprenylierung adaptiert ist.
  9. Pharmazeutische Zusammensetzung nach Anspruch 8, worin Pren eine Farnesyl- oder Geranyl-Geranyl-Gruppe darstellt; A1 eine direkte Bindung oder eine Methylengruppe darstellt; mindestens zwei von Y1, Y2 und Y3 Hydroxy oder Mercapto oder ein Salz davon sind; und n = 1.
  10. Pharmazeutische Zusammensetzung nach Anspruch 9, worin das Polyisoprenylpyrophosphat-Analogon Farnesylphosphonophosphonat ist.
EP91202616A 1991-10-07 1991-10-07 Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations Expired - Lifetime EP0540782B1 (de)

Priority Applications (7)

Application Number Priority Date Filing Date Title
ES91202616T ES2133278T3 (es) 1991-10-07 1991-10-07 Uso de analogos de pirofosfato de poliisoprenilo para inhibir la isoprenilacion de proteinas.
DE69131199T DE69131199T2 (de) 1991-10-07 1991-10-07 Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations
AT91202616T ATE179607T1 (de) 1991-10-07 1991-10-07 Verwendung von polyisoprenyl pyrophosphate analogen zur hemmung des proteinisoprenylations
DK91202616T DK0540782T3 (da) 1991-10-07 1991-10-07 Anvendelse af polyisoprenylpyrophosphatanaloger til inhibering af proteinisoprenylering
EP91202616A EP0540782B1 (de) 1991-10-07 1991-10-07 Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations
JP29089692A JP3518611B2 (ja) 1991-10-07 1992-10-06 蛋白質のイソプレニル化に関連する疾病の治療方法
GR990401883T GR3030795T3 (en) 1991-10-07 1999-07-15 Use of analogues of polyisoprenyl pyrophosphate for inhibiting protein isoprenylation

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EP91202616A EP0540782B1 (de) 1991-10-07 1991-10-07 Verwendung von Polyisoprenyl pyrophosphate Analogen zur Hemmung des Proteinisoprenylations

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AT (1) ATE179607T1 (de)
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DK (1) DK0540782T3 (de)
ES (1) ES2133278T3 (de)
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GB2267494B (en) * 1992-06-02 1995-09-20 Ciba Geigy Ag Trisamidodithionodiphosphates
US5883066A (en) * 1993-06-28 1999-03-16 The Procter & Gamble Company Liquid detergent compositions containing cellulase and amine
WO1995025086A1 (en) * 1994-03-15 1995-09-21 Eisai Co., Ltd. Isoprenyl transferase inhibitors
US5574025A (en) * 1994-10-26 1996-11-12 Merck & Co., Inc. Inhibitors of prenyl-protein transferases
EP1090909A1 (de) * 1999-09-28 2001-04-11 Rijksuniversiteit Leiden Hemmer für Enzyme, die Prenylpyrophosphate umsetzen
JP2001158799A (ja) 1999-09-28 2001-06-12 Rijksuniv Leiden プレニル化ピロリン酸消費酵素の新規な阻害剤
AU1226001A (en) * 1999-11-09 2001-06-06 Alcon Universal Limited Phospholipids of hydroxyeicosatetraenoic acid-like derivatives

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US4871721A (en) * 1988-01-11 1989-10-03 E. R. Squibb & Sons, Inc. Phosphorus-containing squalene synthetase inhibitors
JP2714402B2 (ja) * 1988-07-13 1998-02-16 日清製粉株式会社 癌転移抑制剤
EP0356866A3 (de) * 1988-08-29 1991-03-27 E.R. SQUIBB & SONS, INC. Phosphor enthaltende Squalen-Synthetase-Inhibitoren und Verfahren
US5025003A (en) * 1989-09-18 1991-06-18 E. R. Squibb & Sons, Inc. Isoprenoid phosphinylformic acid squalene synthetase inhibitors

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EP0540782A1 (de) 1993-05-12
DK0540782T3 (da) 1999-11-01
GR3030795T3 (en) 1999-11-30
DE69131199D1 (de) 1999-06-10
JP3518611B2 (ja) 2004-04-12
DE69131199T2 (de) 1999-08-26
ATE179607T1 (de) 1999-05-15
ES2133278T3 (es) 1999-09-16
JPH07188028A (ja) 1995-07-25

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